TY - JOUR
T1 - Further characterization of ATP6V0A2-related autosomal recessive cutis laxa
AU - Fischer, Björn
AU - Dimopoulou, Aikaterini
AU - Egerer, Johannes
AU - Gardeitchik, Thatjana
AU - Kidd, Alexa
AU - Jost, Dominik
AU - Kayserili, Hülya
AU - Alanay, Yasemin
AU - Tantcheva-Poor, Iliana
AU - Mangold, Elisabeth
AU - Daumer-Haas, Cornelia
AU - Phadke, Shubha
AU - Peirano, Reto I.
AU - Heusel, Julia
AU - Desphande, Charu
AU - Gupta, Neerja
AU - Nanda, Arti
AU - Felix, Emma
AU - Berry-Kravis, Elisabeth
AU - Kabra, Madhulika
AU - Wevers, Ron A.
AU - Van Maldergem, Lionel
AU - Mundlos, Stefan
AU - Morava, Eva
AU - Kornak, Uwe
N1 - Funding Information:
Acknowledgments We are grateful to the patients and their family members whose cooperation made this study possible. We would like to thank the family of patient 2 especially for their great contribution and interest in our work. We thank Traute Burmester for her excellent help with fibroblast cultivation from skin biopsies. We additionally thank E. Ntrivalas for providing the ATP6V0A2 antibody. This study was funded by the Fritz Thyssen Stiftung to Uwe Kornak.
PY - 2012/11
Y1 - 2012/11
N2 - Autosomal recessive cutis laxa (ARCL) syndromes are phenotypically overlapping, but genetically heterogeneous disorders. Mutations in the ATP6V0A2 gene were found to underlie both, autosomal recessive cutis laxa type 2 (ARCL2), Debré type, and wrinkly skin syndrome (WSS). The ATP6V0A2 gene encodes the a2 subunit of the V-type H+-ATPase, playing a role in proton translocation, and possibly also in membrane fusion. Here, we describe a highly variable phenotype in 13 patients with ARCL2, including the oldest affected individual described so far, who showed strikingly progressive dysmorphic features and heterotopic calcifications. In these individuals we identified 17 ATP6V0A2 mutations, 14 of which are novel. Furthermore, we demonstrate a localization of ATP6V0A2 at the Golgi-apparatus and a loss of the mutated ATP6V0A2 protein in patients' dermal fibroblasts. Investigation of brefeldin A-induced Golgi collapse in dermal fibroblasts as well as in HeLa cells deficient for ATP6V0A2 revealed a delay, which was absent in cells deficient for the ARCL-associated proteins GORAB or PYCR1. Furthermore, fibroblasts from patients with ATP6V0A2 mutations displayed elevated TGF-β signalling and increased TGF-β1 levels in the supernatant. Our current findings expand the genetic and phenotypic spectrum and suggest that, besides the known glycosylation defect, alterations in trafficking and signalling processes are potential key events in the pathogenesis of ATP6V0A2-related ARCL.
AB - Autosomal recessive cutis laxa (ARCL) syndromes are phenotypically overlapping, but genetically heterogeneous disorders. Mutations in the ATP6V0A2 gene were found to underlie both, autosomal recessive cutis laxa type 2 (ARCL2), Debré type, and wrinkly skin syndrome (WSS). The ATP6V0A2 gene encodes the a2 subunit of the V-type H+-ATPase, playing a role in proton translocation, and possibly also in membrane fusion. Here, we describe a highly variable phenotype in 13 patients with ARCL2, including the oldest affected individual described so far, who showed strikingly progressive dysmorphic features and heterotopic calcifications. In these individuals we identified 17 ATP6V0A2 mutations, 14 of which are novel. Furthermore, we demonstrate a localization of ATP6V0A2 at the Golgi-apparatus and a loss of the mutated ATP6V0A2 protein in patients' dermal fibroblasts. Investigation of brefeldin A-induced Golgi collapse in dermal fibroblasts as well as in HeLa cells deficient for ATP6V0A2 revealed a delay, which was absent in cells deficient for the ARCL-associated proteins GORAB or PYCR1. Furthermore, fibroblasts from patients with ATP6V0A2 mutations displayed elevated TGF-β signalling and increased TGF-β1 levels in the supernatant. Our current findings expand the genetic and phenotypic spectrum and suggest that, besides the known glycosylation defect, alterations in trafficking and signalling processes are potential key events in the pathogenesis of ATP6V0A2-related ARCL.
UR - http://www.scopus.com/inward/record.url?scp=84867581983&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84867581983&partnerID=8YFLogxK
U2 - 10.1007/s00439-012-1197-8
DO - 10.1007/s00439-012-1197-8
M3 - Article
C2 - 22773132
AN - SCOPUS:84867581983
SN - 0340-6717
VL - 131
SP - 1761
EP - 1773
JO - Human genetics
JF - Human genetics
IS - 11
ER -